Study of First TIME Immunotolerance Induction in Severe Hemophilia A Patients With Inhibitor at High Risk of Failure: Comparison With FVIII Concentrates With or Without Von Willebrand Factor - RES.I.S.T. Naive (RESIST NAIVE)

December 15, 2020 updated by: City of Hope Medical Center

Randomised Study of First TIME Immunotolerance Induction in Patients With Severe Type A Haemophilia With Inhibitor at High Risk of Failure: Comparison of Induction of Immune Tolerance With FVIII Concentrates With or Without Von Willebrand Factor Acronym: RES.I.S.T.- Naive

This is a prospective, controlled, randomized, open label study, aimed at comparing FVIII/VWF concentrates with FVIII concentrates at 200 IU/kg daily in their ability to induce immune tolerance in Haemophilia A patients with high responding inhibitors and poor prognosis for success.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

The presence of Factor VIII (FVIII) inhibitor prevents FVIII infusions from working properly and makes treatment of bleeding episodes very difficult. Having an inhibitor is a serious and life-threatening complication in patients with Hemophilia. The usual treatment of patients with FVIII inhibitors involves "immune tolerance induction" (ITI). Immune Tolerance means that the body can accept infused FVIII and that FVIII is again effective in controlling bleeds. ITI involves giving high doses of FVIII regularly until the inhibitor disappears. This treatment is not always effective. The inhibitor persists in about 1 in 5 patients who undergo ITI.

There are 2 types of FVIII concentrates: FVIII concentrates derived from human plasma, which contain the von Willebrand factor, and concentrates of FVIII without VWF (recombinant or plasma derived). Both types of concentrates are commonly used to induce immune tolerance in patients with Hemophilia A. Retrospective studies in subjects with hemophilia and inhibitors at risk for failing ITI, have indicated a higher rate of success if patients were treated with von Willebrand containing factor VIII concentrates. It is not known whether the addition of Von Willebrand factor offers an advantage to achieving immune tolerance.

Study Type

Interventional

Phase

  • Not Applicable

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • ADULT
  • OLDER_ADULT
  • CHILD

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Description

Inclusion Criteria:

  1. severe hemophilia A (FVIII<1%);
  2. male, any age;
  3. high responders (peak inhibitor levels > 5 BU);
  4. any inhibitor level at study enrolment;
  5. ability and willingness to participate in the study;

  6. at least one of the following risk factors for ITI failure:

    • peak inhibitor titer > 200 BU
    • titer at ITI start > 10 BU
    • age > 7 years
    • time between inhibitor occurrence and ITI > 2 years
  7. absence of high risk of cardiovascular, cerebrovascular or other thromboembolic events as deemed by the treating clinician.

Exclusion Criteria:

  1. concomitant systemic treatment with immunosuppressive drugs;
  2. concomitant experimental treatment;
  3. previous ITI attempt;
  4. previous history of myocardial infarction and/or cerebral stroke.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: PREVENTION
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
ACTIVE_COMPARATOR: von Willebrand factor-free FVIII concentrates
Patients treated with FVIII concentrates
Drug: FVIII Concentrates
Patients will be centrally randomized to receive a von Willebrand factor-free FVIII concentrate (recombinant or plasma-derived, monoclonally-purified). The choice of product brand will be based on physician / patients preferences.
Other Names:
  • Xyntha
  • Including but not limited to:
  • Advate
  • Beriate P
  • Hemofil M
  • Helixate
  • Kogenate
  • Kogenate SF
  • Monarch M
  • Monoclate
  • Recombinate
  • Refacto
  • Replenate
ACTIVE_COMPARATOR: FVIII/VWF concentrates
Patients treated with FVIII/VWF concentrates
Drug: FVIII/VWF concentrates
Patients will be centrally randomized to receive a FVIII/VWF concentrate of 200 IU/Kg by one or two bolus injections daily.The choice of product brand will be based on physician / patients preferences.
Other Names:
  • Koate-DVI
  • Emoclot DI
  • Factane
  • 8Y
  • Optivate
  • Alphanate
  • Fahndi
  • Haemate P
  • Humate P
  • Haemoctine SDH
  • Octanate
  • Wilate
  • Including but not limited to:

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Primary end point is the success in inducing immune tolerance, defined as: the abolition of the inhibitor to < 0.6 BU within 33 months of ITI with a factor VIII recovery ≥ 66% and half-life ≥ 6 hrs, and measured after a 72-hour washout period.
Time Frame: 33 months
33 months

Secondary Outcome Measures

Outcome Measure
Time Frame
Absence of relapse, up to 12 months after achievement of Immune Tolerance
Time Frame: 12 months
12 months
Time to achieve partial or complete success as defined in the protocol.
Time Frame: 33 months
33 months
Safety Compliance to treatment
Time Frame: 33 months
33 months
Cost of Care
Time Frame: 12 months
12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

City of Hope Medical Center

Collaborators

CSL Behring
Grifols Therapeutics LLC
Grifols Biologicals, LLC
Charta Foundation
Biotest Pharmaceuticals Corporation

Investigators

  • Principal Investigator: Nadia P Ewing, MD, Clinical Professor of Pediatrics, City of Hope National Medical Center, Dept. of Pediatrics, 1500 E. Duarte Rd. Duarte, CA 91010

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

September 25, 2009

Primary Completion (ACTUAL)

June 25, 2020

Study Completion (ACTUAL)

June 25, 2020

Study Registration Dates

First Submitted

January 15, 2010

First Submitted That Met QC Criteria

January 15, 2010

First Posted (ESTIMATE)

January 18, 2010

Study Record Updates

Last Update Posted (ACTUAL)

December 17, 2020

Last Update Submitted That Met QC Criteria

December 15, 2020

Last Verified

December 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 06201
  • 2008-007016-15 (EUDRACT_NUMBER)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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